Oxidative stress-mediated epigenetic regulation by G-quadruplexes.
Oxidative stress-mediated epigenetic regulation by G-quadruplexes.
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DOI：
10.1093/narcan/zcab038
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发表时间：
2021-09
期刊：
影响因子：
5.1
通讯作者：
Burrows CJ
中科院分区：
文献类型：
--
作者：
Fleming AM;Burrows CJ
许多癌症相关基因受富含鸟嘌呤（G）的序列调控，这些序列能够从典型的双链体结构重折叠为链内G-四链体。这些相同的序列对由碱基切除修复糖基化酶OGG 1和NEIL 1 -3修复的氧化损伤敏感。我们描述的研究表明，在基因启动子G-四链体中的鸟苷碱基的氧化可以导致基因表达的上调和下调，这是位置依赖性的，并涉及碱基切除修复途径，其中第一中间体，脱嘌呤（AP）位点，起着关键作用介导的AP核酸内切酶1（APE 1/REF 1）。APE 1的核酸酶活性在G-四链体处暂停，而这种蛋白质的REF 1能力与激活转录因子如HIF-1α、AP-1和p53结合。该机制已通过体外生物物理研究、全基因组方法和细胞中的报告质粒进行了探索。由G-四链体序列的启动子元件的替换通常会导致上调，但取决于链和精确的位置，下调的例子也found. The氧化应激介导的损伤的影响，在G-丰富的序列增强的效果，无论是积极的还是消极的。基因启动子区富含鸟嘌呤的序列对氧化应激敏感，并可能重折叠成G-四链体。DNA修复过程通过AP内切酶结合和募集激活转录因子的能力影响基因表达。
Many cancer-associated genes are regulated by guanine (G)-rich sequences that are capable of refolding from the canonical duplex structure to an intrastrand G-quadruplex. These same sequences are sensitive to oxidative damage that is repaired by the base excision repair glycosylases OGG1 and NEIL1–3. We describe studies indicating that oxidation of a guanosine base in a gene promoter G-quadruplex can lead to up- and downregulation of gene expression that is location dependent and involves the base excision repair pathway in which the first intermediate, an apurinic (AP) site, plays a key role mediated by AP endonuclease 1 (APE1/REF1). The nuclease activity of APE1 is paused at a G-quadruplex, while the REF1 capacity of this protein engages activating transcription factors such as HIF-1α, AP-1 and p53. The mechanism has been probed by in vitro biophysical studies, whole-genome approaches and reporter plasmids in cellulo. Replacement of promoter elements by a G-quadruplex sequence usually led to upregulation, but depending on the strand and precise location, examples of downregulation were also found. The impact of oxidative stress-mediated lesions in the G-rich sequence enhanced the effect, whether it was positive or negative. Guanine-rich sequences in promoter regions of genes are sensitive to oxidative stress and may refold to G-quadruplexes. The DNA repair process impacts gene expression through the ability of AP-endonuclease to bind and recruit activating transcription factors.